Physical exercise, ß-adrenergic receptors, and vascular
response
Exercício físico, receptores ß-adrenérgicos e resposta vascular
Alexandre Sérgio Silva, Angelina Zanesco*
Introduction
he last decades were marked by the increased pre-valence of cardiovascular risk factors, such as sedentary lifestyle, obesity, and changes in lipid proile, thereby rai-sing the incidence of chronic degenerative diseases, such as hypertension, type 2 diabetes mellitus, and atherosclerosis.1
Some vascular diseases greatly compromise blood low and oxygenation of diferent tissues, causing poor wound hea-ling, infection, and pain, which may result in amputation mainly of the lower limbs, thus representing an important cause of death.2 Venous insuiciency and peripheral arterial
occlusive disease have a high prevalence in the population, especially among the elderly, afecting about 10-40%, and the etiopathogenesis of both conditions is closely associated with endothelial dysfunction.2,3
Evidence shows that aerobic physical training promotes beneicial efects on the prevention and treatment of cardio-vascular diseases and endocrine/metabolic disorders, such as hypertension, diabetes mellitus, dyslipidemia, and atheroscle-rosis.4 One of the mechanisms by which physical exercise
pro-motes these efects is associated with increased blood low on the vessel wall, resulting in increased production and/or bio-availability of nitric oxide (NO) in vascular smooth muscle.5,6
Abstract
Aerobic exercise promotes beneicial efects on the prevention and treatment of diseases such as arterial hypertension, atherosclerosis, venous insuiciency, and peripheral arterial disease. β-adrenergic receptors are present in a variety of cells. In the cardiovascular system, β-adrenergic receptors promote positive inotropic and chronotropic response and vasorelaxation. Although the efect of exercise training has been largely studied in the cardiac tissue, studies focused on the vascular tissue are rare and controversial. his review examines the data from studies using animal and human models to determine the efect of physical exercise on the relaxing response mediated by β-adrenergic receptors as well as the cellular mechanisms involved in this response. Studies have shown reduction, increase, or no efect of physical exercise on the relaxing response mediated by β-adrenergic receptors. hus, the efects of exercise on the vascular β-adrenergic sensitivity should be more deeply investigated. Furthermore, the physiopathology of the vascular system is an open ield for the discovery of new compounds and advances in the clinical practice.
Keywords:β-adrenergic receptors, blood pressure, vascular smooth muscle, physical exercise. Resumo
O exercício aeróbio promove efeitos benéicos na prevenção e tratamento de doenças como hipertensão arterial, aterosclerose, insuiciência venosa e doença arterial periférica. Os receptores β-adrenérgicos estão presentes em várias células. No sistema cardiovascular, promovem inotropismo e cronotropismo positivo cardíaco e relaxamento vascular. Embora os efeitos do exercício tenham sido investigados em receptores cardíacos, estudos focados nos vasos são escassos e controversos. Esta revisão abordará os efeitos do exercício físico sobre os receptores β-adrenérgicos vasculares em modelos animais e humanos e os mecanismos celulares envolvidos na resposta relaxante. Em geral, os estudos mostram resultantes conlitantes, onde observam diminuição, aumento ou nenhum efeito do exercício físico sobre a resposta relaxante. Assim, os efeitos do exercício na sensibilidade
β-adrenérgica vascular merecem maior atenção, e os resultados mostram que a área de isiopatologia vascular é um campo aberto para a descoberta de novos compostos e avanços na prática clínica.
Palavras-chave: Receptores β-adrenérgicos, pressão arterial, músculo liso vascular, exercício físico.
*Departamento de Educação Física, Instituto de Biociências, Universidade Estadual Paulista (UNESP), Rio Claro, SP, Brazil. No conlicts of interest declared concerning the publication of this article.
Physical exercise promotes a direct impact on vascular function, with signiicant beneicial efects on the patient’s quality of life.4 Studies report that patients with peripheral
arterial occlusive disease start to feel less pain and increase walking distance without claudication in response to physi-cal exercise, signiicantly reducing mortality among these pa-tients.7-9 Although there are drugs that also improve walking
ability without claudication, the results are still modest when compared to supervised exercise programs associated with smoking cessation.10 In post-surgical varicose vein patients,
physical exercise appears to be able to restore microvascular endothelial function to levels observed in age-matched heal-thy controls, even in the irst minutes ater exercise.11
In addition to acting on endothelial cells, physical exer-cise reduces sympathetic activity and increases parasym-pathetic activity, leading to an improvement in vascular tone.12 Physical exercise also contributes to morphological
changes of the vessels, modulating the growth of vascular smooth muscle cells, the formation of endothelial cells, and apoptosis reduction and promoting angiogenesis.6 here
are reports of improvement in muscle oxidative activity in patients with peripheral arterial occlusive disease via decreased concentration of short-chain acylcarnitine, an intermediate of oxidative metabolism,13 which contributes
to increase the walking distance without claudication in pa-tients with peripheral arterial occlusive disease performing exercise training.
Adrenergic receptors are also implicated in vascular activity. Stimulation of α and β receptors in response to ex-posure to their agonists promotes constriction or relaxation of arteries and veins.NO production by endothelial cells is partly mediated by activation of β-adrenergic receptors.14
However, little is known about the role that β-adrenergic receptors play in blood vessels and the inluence of physi-cal exercise on these receptors in healthy individuals or pa-tients with diferent pathological conditions, such as athe-rosclerosis, hypertension and diabetes mellitus.
herefore, this review approaches the involvement of
β-adrenergic receptors in vasorelaxation, the efects of phy-sical exercise on the relaxant response, and the molecular mechanisms involved. he study of β-adrenergic receptors ofers an interesting ield of study in the area of vascular physiology, which might open new perspectives in the pre-vention and/or treatment of vascular diseases of diferent etiologies.
Vascular smooth muscle and endothelium
Arterial vessels usually have three layers: the intima, which is in contact with blood elements and consists mainly
of endothelial cells; the media, composed of smooth muscle cells; and the adventitia, composed of ibrous connective tissue, which is the outer coat of the artery. Smooth mus-cle cells are oten spindle-shaped with larger diameters in the core region. he sarcoplasmic reticulum, less developed compared to reticula of other types of muscle cells, is clo-sely associated with the plasma membrane, which explains its involvement in Ca2+ signaling mechanisms and muscle
contraction. he activation of this biochemical cascade of vascular smooth muscle contraction occurs through bin-ding of contractile agents, such as norepinephrine, pheny-lephrine and endothelin, to speciic membrane receptors present in the muscle cell. hese receptors, in turn, activate a protein called G protein that stimulates phospholipase C, present in the cell membrane, which catalyzes the forma-tion of second messengers from membrane phospholipids generating inositol-1,4,5-triphosphate (IP3) and diacyl-glycerol (DAG). IP3 binds to its receptors located in the sarcoplasmic reticulum, releasing to the cytosol Ca2+ ions
present within this organelle. he DAG molecule activates a protein called protein kinase C (PKC), which, in turn, phosphorylates proteins bound to L-type calcium channels, favoring the inlux of extracellular Ca2+ to the intracellular
medium. hese two messengers cause an elevation in Ca2+
concentration, enabling actin-myosin interaction and pro-ducing contraction of vascular smooth muscle.15
he relaxation of vascular smooth muscle is triggered by diferent agents produced by endothelial cells, including prostacyclin, endothelium-derived hyperpolarizing factor (EDHF), and NO. NO is considered the most potent va-sodilator produced by the endothelium, and control of its production is directly related to various diseases, such as hypertension, atherosclerosis, and coronary artery disea-se.16 Several mediators and neurotransmitters can promote
the release of NO by endothelial cells, such as acetylcholine, bradykinin and norepinephrine, through activation of its speciic receptors.
More recently, hydrogen peroxide (H2O2) and
hydro-gen sulide (H2S) have been highlighted in vascular research
as important mediators in the relaxant response of diferent vessels.17,18 hus, the discovery of these molecules in
vascu-lar function opens a relevant ield on the therapeutic poten-tial of thromboembolic disease.
β-adrenergic receptors
Adrenergic receptors were initially divided into two bro-ad categories, α and β. Subsequently, they were subdivided into subtypes α1, α2, β1, β2, and β3 by using subtype-selective
their protein structures. α-adrenergic receptors are further subdivided into α1A, α1B, α1D, α2A, α2B, and α2C.
19-21
β-adrenergic receptors are present in diferent cells, acting on a variety of functions, including modulation of hormone release, metabolic control, and cardiovascular regulation. Stimulation of β-adrenergic receptors, in the islets of Langerhans, increases glucose in humans, thus β2
-adrenergic agonists are used in the treatment of hypoglyce-mia.22,23 In adipocytes, β
3 receptors have been shown to act
on leptin release.24 Moreover, the balance between
lipoge-nesis and lipolysis is associated with stimulation of α- and
β-adrenergic receptors, respectively.25
Particularly in the cardiovascular system, β-adrenergic receptors promote positive cardiac chronotropic and ino-tropic response (increasing heart rate and contractile force, respectively) and vasodilation. hese actions are triggered by the binding of catecholamines (epinephrine and nore-pinephrine, released from autonomic ibers) to diferent
β-adrenergic receptor subtypes present in cardiac muscle cells and blood vessels. Currently, at least three β-adrenergic receptor subtypes are recognized: β1, β2, and β3. β1 and β2
receptors were the irst to be classiied based on the use of subtype-selective agonists and antagonists.26β
3-adrenergic
receptors were irst described in adipocytes,27 and their
presence was subsequently demonstrated in cardiac tissue, mediating chronotropism,28 and also in blood vessels,
pro-moting vasodilation.14 he classiication of β-adrenergic
receptors was possible through the synthesis of selective agonists, such as BRL 37344 and CL 316243.29,30 he
exis-tence of a fourth β-adrenergic receptor, called β4, which
would mediate muscle glucose uptake and cardiac chrono-tropism and inochrono-tropism in humans and rats, was proposed by various authors.31-33 However, other studies report that
β1 receptors may present an altered conformational state,
in which they lose ainity for their speciic ligands and start to have ainity for other agonists that activate β3 and also
β4 receptors, such as the agonist CGP 12177.
34-38 hus, the
existence of β4-adrenergic receptor remains unclear.
he ainity and eicacy of β-adrenergic drugs may also vary depending on the conformational state of recep-tors and their mechanisms for coupling to proteins and se-cond messengers present within the cells that constitute the tissue.39,40 he density of β-adrenergic receptors also varies
greatly among diferent cells and tissues and according to the species studied.41-44
Vascular β-adrenergic receptors
Early studies investigating vascular beds have shown the existence of two β-adrenergic receptor subtypes, β1 and
β2, in diferent arteries and veins. It was observed that the
vasodilator response was mediated predominantly by β2
-adrenergic receptors compared with β1-receptor subtypes,
with an order of potency of epinephrine > norepinephrine > phenylephrine,45-47 although this classiication of potency
does not apply to all vascular beds.5 Some studies show that
β1-adrenergic receptors also promote vasodilation,
48,49
whe-reas other studies show that β3-receptor subtypes
participa-te in the vasodilator response of arparticipa-teries of various species, such as human coronary arteries,14,50 rat aorta,51 and canine
pulmonary arteries.52-54 In rat aorta, it was demonstrated
that some relaxant responses appear to be mediated by a population of atypical receptors (presumably β4),
throu-gh the use of conventional agonists/antagonists that sti-mulate β1-, β2-, and β3-receptor subtypes.
55-57 On the other
hand, other studies failed to conirm the participation of
β3-adrenergic receptors and of this atypical receptor (β4) in
this preparation.58,59In rat mesenteric arteries, β
4-adrenergic
receptor also seems to be present,60 but these data were not
conirmed in a subsequent study in these arteries.48
Studies involving femoral and brachial arteries are scar-ce compared to more scar-central and larger arteries, such as the aorta and mesenteric artery. In one of these few studies, the presence of β1- and β2-adrenergic receptors was observed
through the use of selective agonists/antagonists in porcine femoral artery.61 On the other hand, in rabbit femoral
arte-ries, only β2-receptor subtypes were shown to mediate the
vasodilator response.62
Mechanism of action of β-adrenergic receptors
The multiple intracellular signaling pathways in response to the activation of β-adrenergic receptors in blood vessels modify according to the β-adrenoceptor subtype that is mediating relaxant responses and to the vascular bed studied.61 Although the activation of cyclic
adenosine monophosphate (cAMP) is the classic pathway for the vasodilator response to β-adrenergic stimulation, dependent and independent mechanisms of formation of this second messenger contribute to the relaxant respon-se induced by the activation of therespon-se receptors.63,64 For
details, see Figure 1.
Signaling pathway: cAMP-protein kinase A
intracellularly by seven transmembrane domains. The relative size of N- and C-terminal chains and of the third intracellular loop varies considerably from re-ceptor to rere-ceptor.65,66 The third intracellular loop of
β-adrenoceptors is the site for coupling of these recep-tors to G protein. G proteins are heterotrimers, consis-ting of one hydrophilic α-subunit and two hydrophobic subunits, β and γ. In the absence of agonists, when G protein is inactive, a molecule of guanosine diphospha-te (GDP) is bound to the α-subunit, forming a complex associated with β- and γ-subunits. In the presence of agonists, the activated receptor interacts with G protein and induces the conversion of GDP into guanosine tri-phosphate (GTP) in the α-subunit. After binding to GTP, the α-subunit dissociates from βγ-subunits and becomes active. The α-subunit remains free until GTP hydroly-sis and formation of GDP occurs, leading to its reasso-ciation with βγ-subunits. The α-subunit of Gs protein, when activated, leads to stimulation of adenylyl cyclase, which leads to the formation of cAMP second messenger from ATP breakdown. cAMP activates protein kinase A that will promote reduction in intracellular Ca2+
concen-tration in vascular smooth muscle cells, with consequent vasodilation.66,67 For details, see Figure 1.
Signaling pathway by activation of calcium-dependent potassium channels
Maintenance of relaxant activity of the aorta in res-ponse to isoprenaline, even in the presence of SQ 22,536 (an adenylyl cyclase inhibitor), supports the existence of cAMP-independent mechanism in certain vessels.51 In
addition, relaxation is abolished in the presence of iberioto-xin, a K+ channel blocker, suggesting the involvement of
lar-ge-conductance Ca2+-activated K+ channels (MaxiK). hese
data are consistent with a previous study that demonstrated the importance of K+ channels in the relaxant response of
the basilar artery of the guinea pig.68 Additionally,
relaxa-tion was shown to be dependent on MaxiK channels only for responses mediated by β1-andβ2-adrenergic receptors,
whereas, for β3 receptors, Kv channels do not appear to be
involved.51
he mechanism by which activation of β-adrenergic receptors promotes relaxation is carried out through the activation and opening of K+ channels, allowing their
ex-tracellular release, which, in turn, causes reduction in membrane potential, leading to cell hyperpolarization. his results in the closure of voltage-dependent Ca2+ channels.
Ca2+ channel closure by membrane hyperpolarization
cau-ses a reduction in the Ca2+-calmodulin complex and in the
phosphorylation of the myosin light chain, leading to rela-xation.10 For details, see Figure 1.
Signaling pathway: nitric oxide-cGMP
Another signaling pathway of β-adrenergic receptor-mediated, cAMP-independent relaxation is the endo-thelial pathway. Vasodilator response by stimulation of
β-adrenergic receptors has been shown to be partially69,70
or completely14 inhibited by endothelium removal or in
the presence of NO synthase inhibitors, such as L-NAME. Furthermore, inhibition of soluble guanylate cyclase in vessels without endothelium eliminates the vasodilator res-ponse, whereas addition of sodium nitroprusside restores vasorelaxation. hus, these studies show that NO produced by endothelial cells is involved in β-adrenoceptor-induced relaxation.
he mechanisms by which β-adrenergic receptors pro-mote NO release seem to involve several signaling pathways, such as mitogen-activated protein kinase (MEK), p42/p44 mitogen-activated protein kinase (MAPK) or ERK1/2, and phosphatidylinositol 3-kinase (PI3K), both in humans and laboratory animals.71-73 he activation of these enzymes by
β-adrenergic receptors leads to activation of endothelial NO synthase (eNOS) present in endothelial cells, which, Figure 1 – Mechanisms by which β-adrenergic receptors promote
va-sorelaxation.
Classic pathway of G-protein activation of β-adrenergic receptors, activation of adenylyl cyclase, and formation of cAMP, which, in turn, activates protein kinase A (panel B). Two other pathways include activation of a variety of proteins that activate eNOS and result in NO formation (panel A) and opening of potassium channels, promoting membrane hyperpolarization, which, in turn, promotes the closure of voltage-dependent calcium channels (panel C). Both the classic pathway, cAMP formation, and voltage-dependent calcium channel activating pathway occur in vascular smooth muscle, whereas NO formation occurs in the endothelium.
in turn, will promote oxidation of a terminal nitrogen of the guanidine group of L-arginine, forming equimolar amounts of NO and L-citrulline. Once formed, NO difuses rapidly from endothelial to smooth muscle cells, where it interacts with the heme group of soluble guanylate cyclase, stimulating its catalytic activity and leading to the forma-tion of cyclic guanosine monophosphate (cGMP), which, in turn, reduces intracellular Ca2+ levels. For details, see Figure
1. he mechanisms by which NO/cGMP pathway induces vasodilation include inhibition of IP3 generation, increased sequestration of cytosolic Ca2+, dephosphorylation of the
myosin light chain, inhibition of Ca2+ inlux, protein
kina-se activation, stimulation of membrane Ca2+-ATPase, and
opening of K+ channels.74
Phosphodiesterases and vascular disease
he importance of cAMP and cGMP as mediators of various cellular functions, including regulation of vascular tone, proliferation of smooth muscle cells, and inhibition of platelet adhesion and aggregation, has given rise to several studies for the development and synthesis of various com-pounds in order to increase or control intracellular levels as a treatment for several diseases, such as erectile dysfunc-tion, cardiac and vascular diseases.5
Intracellular cAMP and cGMP levels are controlled by enzymes called phosphodiesterases, which catalyze hydrolysis of these mediators, leading to the formation of 5’cAMP and 5’cGMP, respectively. There are at least 11 isoforms of phosphodiesterase, including phospho-diesterases type 3 and 5, which are highly selective for degradation of cAMP and cGMP, respectively.75 The
compound cilostazol, a selective inhibitor of phospho-diesterase 3, has been widely used in clinical practice for the treatment of intermittent claudication in peripheral arterial occlusive disease, promoting increased intra-cellular cAMP levels. The administration of cilostazol promotes potent vasodilation and inhibition of plate-let aggregation, improving pain and walking ability.2,10
Furthermore, β-adrenergic receptor activation leads to activation of two important second messengers, cAMP and cGMP, whose therapeutic target is the focus of ma-jor drug companies, highlighting the importance of in-vestigating the role that these receptors play in vascular disease. Recently, German researchers have synthesized the compounds BAY 41-2272 and BAY 58-2667, direct soluble guanylate cyclase activators, which have proven to be potent vasodilators with great therapeutic potential for vascular diseases such as thrombosis and peripheral arterial occlusive disease.76
hus, drug therapy for vascular diseases still requires further advances, and its association with non-pharmaco-logical therapy, such as physical exercise, deserves attention within the area of angiology, since physical exercise promo-tes important changes in the vascular system, especially in the endothelium.
Physical exercise and endothelial activation
Physical exercise is characterized by skeletal muscle contraction, and during exercise performance signiicant cardiovascular alterations occur, such as: increased blood low into the muscles in activity, reduction in peripheral vascular resistance proportional to the increase in cardiac output, and, consequently, increased systolic blood pres-sure. To adjust all cardiovascular alterations that physical exercise causes, there are mechanisms for neural and humo-ral regulation. Humohumo-ral factors that will cause reduction in peripheral vascular resistance and, consequently, in blood pressure are primarily dependent on the endothelium.16
Increased pulsatile blood low and pressure that blood exerts on the vascular wall produce the so-called shear stress, which acts on the intima of vessels where endothe-lial cells are found. Shear stress is a powerful stimulus for the generation of the vasodilator agent NO in the vascu-lar system. Associated with this phenomenon, physical exercise is an important stimulus to increase blood low and, consequently, promotes increased NO production that triggers beneicial efects, such as vasorelaxation and inhibition of platelet aggregation, preventing diseases such as hypertension and atherosclerosis.6 NO plays a
protec-tive role in the atherosclerosis process by two signaling pathways. First, NO prevents the formation of oxidized LDL-cholesterol molecules, through its antioxidant action (which is concentration-dependent), decreasing the forma-tion of reactive species of oxygen, which are fundamental for the process of oxidation of LDL-cholesterol molecules; second, by its inhibitory action on platelet adhesion and ag-gregation, preventing thrombus formation and subsequent partial or total ischemia of the tissues involved.6 Studies
evaluating hypercholesterolemic animals showed increased expression of the antioxidant enzyme superoxide dismuta-se (SOD) and better relaxant dismuta-sensitivity through vascular
β-adrenoceptor-activated NO/cGMP pathway in chronic response to exercise.77,78
the cell wall and convert mechanical stimuli into chemi-cal stimuli for eNOS activation.16 he pathways involved
in this process are related to the activation of PKC, cSrc, and Akt/PI3K, which phosphorylate eNOS activating it.79
Shear stress-induced NO production occurs regardless of Ca2+ presence, since Akt protein reduces eNOS sensitivity
to this ion. he ability of endothelial cells to perceive and respond to changes in blood low is an essential factor in the regulation of vascular tone and involves the activation of cell growth factors, promoting the remodeling of the ar-terial wall and maintenance of endothelial integrity.6 hus,
one of the beneicial efects of regular physical activity is closely related to its ability to stimulate NO synthase by en-dothelial cells and, consequently, to control blood pressure. Increased NO production also promotes antithrombotic efects, preventing thromboembolic diseases and atheros-clerosis, a phenomenon that is due to inhibition of platelet aggregation by NO.5,6
Efects of physical activity on vascular β-adrenergic sensitivity
he efects of exercise on vasomotor function have been extensively studied using both vasoconstrictors, such as no-repinephrine and phenylephrine,80,81 and vasodilator agents,
such as acetylcholine and bradykinin.82-84 Norepinephrine
induces vasoconstriction by activating α-adrenergic recep-tors present within vascular smooth muscle cells, whereas acetylcholine promotes vasodilation by activating mus-carinic receptors present within endothelial cells. On the other hand, information about the efects of exercise on
β-adrenoceptor-mediated vasodilator responses is much more scarce, and these few conlicting data show reduced, increased or no efect of physical exercise on the relaxant response. Most existing studies associate relaxant responses of β-adrenergic receptors with the aging process85-88 or
car-diovascular diseases.89-93
he irst studies analyzing the involvement of vascu-lar β-adrenergic receptors in response to physical trai-ning date from the late 1970s and have investigated vas-cular reactivity in response to chronic use of β-blockers in exercise-trained and sedentary rats.94 It was observed
that trained animals without β-blockade showed higher skin temperature when exposed to 5 °C room temperatu-re, in addition to increased vasodilator response to isopre-naline, as judged from the increase in body temperature during a training period. he author suggested increased sensitivity of β2-adrenoceptors or decreased sensitivity
of α-adrenoceptors as an explanation for these pheno-mena.Subsequent studies used blood low and coronary
vascular resistance to access the efects of β-adrenoceptor blockade. It was demonstrated that the β2-adrenergic
re-ceptor selective antagonist ICI 118.551 signiicantly de-creased coronary blood low velocity and inde-creased late diastolic coronary resistance in dogs during a running session.95 hese data showed the important participation
of β-adrenergic response in the relaxant response of co-ronary arteries during exercise.A later study conirmed these results and even showed that coronary resistance and diameter appeared to be also afected by α-adrenergic receptor activity, since the application of phentolamine (a non-selective α-adrenoceptor antagonist) with proprano-lol (a non-selective β-adrenoceptor antagonist) reduced the vasoconstrictor efect of β-adrenoceptor blockade du-ring exercise.96
More recently, studies have been conducted with ol-der animals showing that exercise improved sensitivity of β-adrenergic receptors when the vasodilator response mediated by these receptors had been previously reduced by the aging process.97 Thus, the results showed that a
6-week training program of 5 days/week swimming exer-cise improved vasodilator response to the non-selective
β-adrenoceptor agonist isoproterenol, in coronary arte-ries, compared with the sedentary group. Another study, conducted with old and young rats, showed that a 10- to 12-week treadmill program of 5 days/week running exer-cise, with 60-minute sessions, improved vasodilator res-ponse to isoproterenol in gastrocnemius muscle vessels from old rats, but not in young animals.98 Collectively,
these studies show the beneficial effects of physical exercise on vascular sensitivity in the aging process. However, β-adrenoceptor responsiveness to exercise is not homogeneous, depending on several factors, such as the region of vascular bed to be studied (regions of diffe-rent diameters in the same artery may respond differen-tly to physical exercise).99Another important variable is
the type of artery studied; resistance vessels (forearm) or conductance vessels (brachial artery) showed different responses in relation to blood flow both to dependent agonist (acetylcholine) and to endothelium-independent sodium nitroprusside.96 Likewise, there
may be differences in responses according to the animal studied.
hus, studies related to relaxant responses mediated by
Conclusions
he efects of exercise on the vasodilator response me-diated by β-adrenergic receptors are conlicting.Overall, previous studies show improvement in vascular reactivity to β-adrenoceptor agonists in response to exercise in old animals, but studies involving vascular diseases are scarce and less conclusive. For a better understanding of the efects of physical exercise on vascular β-adrenergic sensitivity, signaling pathways, such as cAMP, cGMP, and ion chan-nels, should be considered and investigated, since factors such as oxidant activity and functional status of the endo-thelium are involved in the activation of these receptors. Collectively, the existing data show that the area of vascular pathophysiology is an open ield for the discovery of new compounds and advances in clinical practice.
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